Due to the absence of effective therapies, pancreatic cancer is the fourth leading cause of cancer deaths in both men and women. This study focuses on the development of new small molecule inhibitors targeting Focal Adhesion Kinase against pancreatic cancer. Focal Adhesion Kinase (FAK) has been shown to play an important role in tumor cell survival, including pancreatic cancer, making FAK an excellent target for anti- cancer therapy. Recently, a novel small molecule autophosphorylation FAK inhibitor (1,2,4,5- Benzenetetraamine tetrahydrochloride) called Y15 has been developed by our group that directly and specifically decreased FAK autophosphorylation in vitro and significantly inhibited pancreatic tumor growth in vivo. Y15 inhibitor has a novel mechanism of action; its advantage over existing therapeutic approaches is that that it targets the autophosphorylation site (Y397) of FAK. Y15 is highly specific and non-toxic. The objective of the proposal is to synthesize the novel chemical derivatives of Y15 to effectively and specifically inhibit FAK autophosphorylation, with the aim of developing therapies that can be used in future pre-clinical and clinical trials to treat pancreatic cancer. To develop new FAK inhibitors with increased pharmacological properties, we will synthesize focused libraries that will be screened by multiple tests to identif Y15 derivatives with the best biological and pharmacological properties. The first aim is to synthesize chemical derivatives of the small molecule FAK inhibitor Y15 for structure activity relationship studies and pharmacological optimization. The second aim is to test these novel inhibitors for specificity and efficacy on FAK autophosphorylation activity in vitro, and to test their ability to inhibit pancreatic cancer and cancer stem cell viability, clonogenicity, cancer stm sphere formation, motility, and invasion, and to induce cell cycle arrest and apoptosis. The third aim is to perform ADMET and PK studies to develop new FAK inhibitors with the best pharmacological properties. The outcome is to obtain the lead novel Y15 derivatives with the highest efficacy in blocking FAK activity and blocking pancreatic cancer and cancer stem cell functions for future pre-clinical and clinical trials. This study will have a strong impact on the field, leading to the development of novel small molecule FAK inhibitors with the best pharmacological properties to block pancreatic cancer and cancer stem cells. The proposed project is an integrated effort of medicinal chemists, structural biologists, biochemists and oncologists of Roswell Park Cancer Research Institute and CureFAKtor Pharmaceuticals to develop novel FAK-targeted therapies against pancreatic cancer.